The role of CD28 homologue CTLA4 in T cell activation has been obscure and controversial. Recent findings suggest that it plays a critical role in down regulation of T cell responses. The mechanism of this down-regulation is not known. The overall aim of this project is to test the hypothesis that the outcome of T cell stimulation is regulated by a complex and dynamic integration of antigen specific signals from the TCR, co-stimulatory signals from CD28 and attenuating signals from CTLA4. One implication of this hypothesis is that CTLA4 may play an important role in peripheral self tolerance and another is that CTLA4 might serve as a target for the manipulation of immune responses. The specific aims art 1) to examine the role of CTLA4 in regulation of early stages of T cell activation; 2) to examine the CTLA4 role in later stages of T cell responses; 3) to determine the basis for the lympho-proliferative disorder that occurs in CTLA4 KO mice; 4) to determine the effectiveness of CTLA4 blockade as a vaccine strategy.